Lacosamide chemically known as (R)—N-benzyl-2-acetamido-3-methoxypropionamide or (2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide as shown in Formula I. It is an amino acid derivative having analgesic and anticonvulsant property.

Lacosamide was developed by Union Chimique Belge (UCB) Pharma and is marketed under brand name Vimpat. It was approved by USFDA in October 2008 as an adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older.
Several methods and Schemes have been developed and disclosed in prior art, for the preparation of lacosamide. Lacosamide has been disclosed for the first time in the U.S. Pat. No. 5,773,475 (Now Reissued as U.S. RE38551) by Research Corporation Technologies. According to this patent, lacosamide is prepared in three different methods which is described below.
Scheme-1:
D-Serine (II) was esterified under acidic condition with methanol, to provide the corresponding ester (III) which was reacted with benzylamine to form the corresponding amide (W). Acylation of the free amino group with acetic anhydride and chiral resolution provide compound (V). O-methylation of (V) using methyl iodide in presence of silver oxide yields Lacosamide (I) in about 4 days when the reaction is carried out at room temperature, as illustrated in example 1 column 12, lines 9-13.

This method suffers from several disadvantages such as loss of material during resolution and use of hazardous reagents such as methyl iodide and expensive ones such as silver oxide. All these factors combined together makes it unsuitable for the large scale manufacturing of Lacosamide.
Scheme-2:
In this scheme acetylation of D-serine (VI) was carried out using acetic anhydride in acetic acid to give N-acetyl-D-serine (VII), which on treatment with isobutyl chloroformate in presence of N-methylmorpholine in tetrahydrofuran at −78° C., followed by reaction with benzylamine to yield (2R)-2-acetamido-N-benzyl-3-hydroxypropanamide (V). Compound V was purified by flash column chromatography and followed by alkylation with methyl iodide in the presence of silver oxide in acetonitrile to provide Lacosamide (I). This methylation was carried out at room temperature for 4 days as illustrated in example 2(b), column 13, lines 1-5

Use of column chromatography is time consuming normally not used in plants and low temperature of −78° C. is difficult on plant scale.
Scheme-3:
This scheme comprises amino group protection of D-serine with benzyloxycarbonyl chloride to yield N-Benzyloxycarbonyl-D-serine (VIII), which on alkylation using methyl iodide in the presence of silver oxide in acetonitrile yields (2R)-methyl-2-(benzyloxycarbonylamino)-3-methoxypropanoate (IX) which was purified by flash column chromatography and hydrolyzed to give (2R)-2-(benzyloxycarbonylamino)-3-methoxypropanoic acid (X). Conversion of VIII to IX was carried out at room temperature for 24 hours as illustrated in example 5(b), lines 34-38. Compound (X) was treated with isobutyl chloroformate −78° C. in THF in presence of N-methylmorpholine followed by reaction with benzylamine to yield the compound (2R)-benzyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate (XI). Deprotection of N-protecting group provides free amine which was subsequently acetylated with acetic anhydride in the presence pyridine and DMAP to give crude Lacosamide (I) which was purified by flash column chromatography to give pure Lacosamide (I).

Above scheme suffers from various drawbacks such as lengthy synthesis, use of column chromatography for the purification of intermediate and final product, reactions at low temperature (−78° C.), unstable intermediate (compound XII) and.
Various processes are also known in the literature for the synthesis of Lacosamide. U.S. Pat. No. 7,884,134 discloses a process for the preparation of Lacosamide of Formula-I which includes O-methylation of N-Boc-D-serine (XIII) using dimethyl sulfate in presence of butyl lithium or with dimethyl sulfate using phase-transfer catalyst and sodium hydroxide to obtain compound XIV. Conversion of compound XIII to XIV was carried out at less than −10° C. Reaction mixture was aged at 0-5° C. for 9 hours as illustrated by example 1 in column 10-11. Compound XIV was reacted with benzylamine using mixed anhydride method disclosed earlier to get the compound (2R)-tert-butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate (XV). Deprotection of the compound XV with hydrochloric acid yields the compound (2R)-2-amino-N-benzyl-3-methoxy-propanamide (XII), which on acetylation yields the compound Lacosamide of Formula-I. The reaction sequence is as given in Scheme-4.

Scheme 4 has disadvantages such as low temperature reaction conditions, use of highly corrosive, hazardous and costly n-Butyl lithium and unstable intermediates such as compound of formula XII.
U.S. Pat. No. 8,093,426 discloses a process for preparation of Lacosamide of Formula-I which involves protection of hydroxyl group of D-serine using trimethylsilyl chloride followed by protection of amino group with trityl chloride and subsequently deprotecting hydroxyl group to isolate N-trityl-D-serine (XVI). Compound XVI is reacted with methyl iodide in the presence of sodium hydride and imidazole at −15 to −5° C. for about 3 hours, to obtain O-methyl-N-trityl-D-serine (XVII) followed by reaction of XVII with isobutyl chloroformate in presence of N-methylmorpholine at −15° C. and reaction with benzylamine to yield (2R)—N-benzyl-3-methoxy-2-(tritylamino)propanamide (XVIII). Compound XVIII on deprotection yields (2R)-2-amino-N-benzyl-3-methoxy-propanamide XII, which on acetylation with acetic anhydride in the presence of dimethylaminopyridine yields Lacosamide of Formula-I. The reaction sequence is given in Scheme-5.

This synthetic sequence suffers drawbacks such as lengthy process, lower temperature for carrying out amidation reaction, use of hazardous Methyl iodide. All these factors pose serious practical problems for large scale production. Although the overall yield is not described in U.S. Pat. No. 8,093,426, it is very low and is about 16%.
WO2014068333 disclosed a method for the preparation of Lacosamide wherein the racemic compound XIX was subjected to kinetic resolution using N-formyl-L-leucine followed by N-acetylation with isopropyl acetate in presence of sodium acetate to obtain Lacosamide (Scheme-6).

This approach also suffers from disadvantages such as loss of 50% material during resolution, use of costly resolving agent and lower yield in acetylation stage. Moreover, the final product obtained was purified using Dean-stark assembly which is a tedious method and not suitable for large scale.
In the method described by U.S. Pat. No. 8,907,132, (R)-2-amino-N-benzyl-3-hydroxypropanamide (IV) was reacted with acetic anhydride in DCM to yield compound (V) which on treatment with dimethyl sulphate in toluene and aq. NaOH under phase transfer condition give Lacosamide (I). The reaction sequence is depicted in Scheme 7. No methodology or means are described by U.S. Pat. No. 8,907,132 to understand when the reaction of conversion of V to I would get over, although the reaction necessitates the use of Phase transfer catalyst (PTC).

Although the overall yield is not described in U.S. Pat. No. 8,907,132, it is very low and is about 33%. The sequence teaches a reaction to prepare N-Boc-D-serine at 20-25° C. after stirring for 10 hours.
In 893/MUM/2011, D-serine was converted to N-Boc-D-Serine in water, 1,4-dioxane mixture under basic condition using Boc-anhydride. Compound XIII was treated with isobutyl chloroformate and benzyl amine to yield compound (XX) which is subsequently subjected to O-methylation using dimethyl sulphate under phase transfer conditions to give compound (XV), the duration of the reaction being 14 hours as illustrated in example step 3. This was further deprotected using conce. HCl and the free base was converted to its acyl derivative i.e Lacosamide. The reaction sequence is depicted in Scheme-8.

Above sequence suffers from long reaction time like 14 hours to prepare N-Boc-D-serine (compound XIII), subzero temperatures in the amidation reaction and isolation of free base (compound XII).
U.S. Pat. No. 8,796,488 describes a process to prepare lacosamide in which racemic N-acyl-D-serine (XXIII) was reacted with benzyl amine in THF to yield compound of formula (XXIV) which on methylation using methyl p-toluene sulphonic acid in THF and aq. NaoH gives compound (XXV). This conversion necessitates the use of PTC. N-acyl protection of Compound of formula (XXV) was deprotected suing dil. HCl in DCM to yield (XXVI) which on chiral resolution gives chiral salt as shown in compound (XXVII). Compound (XXVII) is acylated using acetic anhydride in tert-butyl methyl ether to give Lacosamide (I). The reaction scheme is depicted in Scheme-9.

Drawbacks of this sequence are loss of material during chiral resolution, long reaction times and expensive chiral agents like 2-(S)-chloromandelic acid and which makes above sequence of reaction unsuitable for the scale up.
U.S. Pat. No. 8,748,660 describes a process in which (S)-benzylglycidyl ether (XXVIII) is regioselectively opened under basic condition in methanol to give compound (XXIX) which in turn is converted to azide derivate (XXX) using diisopropyl azadicarboxylate, triphenyl phosphine and diphenylphosphoryl azide in toluene. The azide derivative (XXX) on reduction using Pd(OH)2 and Hydrogen gas in presence of Boc-anhydride yields compound (XXXI). Compound of formula (XXXI) on oxidation with sodium hypochlorite in presence of catalytic TEMPO in acetonitrile give compound (XIV) which on reaction with isobutyl chloroformate, NMM and benzyl amine in THF at −78° C. gives compound (XV). Compound of formula (XV) was deprotected using TFA in DCM and subsequently acylated using acetic anhydride in presence of sodium carbonate in toluene to give Lacosamide (I). The reaction sequence is depicted in Scheme-10.

Above reaction scheme suffers from long reaction times, expensive reagents, cryogenic reaction and numbers of steps involved, rendering it not so suitable for large scale production.
In view of the preparation methods available for lacosamide and considering the pitfalls of the prior art in which complex methodologies are applied, there is a need for simple and cost effective process for the preparation of lacosamide that eliminates racemization of intermediate compounds and provides improved efficiency per reaction volume in terms of yield, purity and chiral purity.